This application claims priority under 35 U.S.C. xc2xa7119 of FR-99/09267, filed Jul. 16, 1999, hereby expressly incorporated by reference.
1. Technical Field of the Invention
The present invention relates to the administration of at least one hydroxystilbene compound, or composition comprised thereof, to an individual subject in need of such treatment, to reduce or even inhibit the glycation of proteins, particularly the proteins of the skin and/or of the structures associated therewith.
2. Description of the Prior Art
Glycation is a non-enzymatic process involving a saccharide (glucose or ribose) which reacts according to the Maillard reaction with an amino group of an amino acid residue (for example such as lysine), particularly an amino acid residue of a protein, to form a Schiff""s base. This Schiff""s base, after undergoing an Amadori molecular rearrangement, can lead, by a series of reactions, to bridging, particularly intramolecular bridging such as, for example, of pentosidine type.
This phenomenon increases uniformly with age. It is characterized by the appearance of glycation products whose content increases uniformly as a function of age. The glycation products are, for example, pyrraline, carboxymethyllysine, pentosidine, crossline, Nxcex5(2-carboxyethyl)lysine (CEL), glyoxallysine dimer (GOLD), methylglyoxallysine dimer (MOLD), 3DG-ARG imidazolone, versperlysines A, B and C, threosidine or the advanced glycosylation end products (or AGEs).
The glycation of proteins is thus a universal phenomenon, which is well known to occur in the skin, particularly in its dermal component, but which also occurs in the structures associated therewith such as the nails or the hair, particularly on keratins and more generally in any protein system provided that the conditions required for glycation are satisfied.
Human skin consists of two components, namely, a superficial component, the epidermis, and a deep component, the dermis.
Natural human skin is principally composed of three types of cell: the keratinocytes, which constitute the vast majority, the melanocytes and the Langerhans cells. Each of these cell types contributes, by virtue of its intrinsic functions, towards the essential role played in the body by the skin.
The dermis provides the epidermis with a solid support. It is also the nourishing factor of the epidermis. It consists principally of fibroblasts and of an extracellular matrix itself composed of different extracellular proteins, among which are, in particular, collagen fibers, elastin and various glycoproteins This assembly of extracellular components is synthesized by the fibroblasts. Leukocytes, mastocytes and tissue macrophages are also found in the dermis. Finally, the dermis contains blood vessels and nerve fibers.
Taking account of their activity in the synthesis of the extracellular matrix proteins (proteoglycans, collagen fibers and other structural glycoproteins), the fibroblasts are the principal factors involved in the structural development of the dermis.
The collagen fibers provide the dermis with solidity. They are very strong but are sensitive to certain enzymes generally known as collagenases. In the dermis, the collagen fibers consist of fibrils bonded together, thus forming more than ten different types of structure. The structure of the dermis is essentially due to the overlapping of the packed collagen fibers. The collagen fibers contribute in respect of the tonicity of the skin. The collagen fibers are regularly renewed, but this renewal decreases with age, thus promoting, especially, a thinning of the dermis. It is also accepted that extrinsic factors such as ultraviolet radiation, tobacco or certain treatments (retinoic acid and derivatives, glucocorticoids, vitamin D and derivatives, for example) also have an effect on the skin and on its collagen level.
As regards the dermal component of the skin, glycation intervenes mainly in the dermis, on the collagen fibers, according to the process described above. The glycation of collagen increases uniformly with age, resulting in a uniform increase in the content of glycation products in the skin.
Without wishing to be bound to any particular theory in respect of aging of the skin, it should be noted that other modifications of collagen which might also be a consequence of glycation, such as a reduction in heat-denaturation, an increase in the resistance to enzymatic digestion and an increase in intermolecular bridges, have been demonstrated in the course of aging of the skin (Tanaka S. et al., 1988, J. Mol. Biol., 203, 495-505; Takahashi M. et al., 1995, Analytical Biochemistry, 232, 158-162). Furthermore, modifications due to the glycation of certain constituents of the basal membrane such as collagen IV, laminin and fibronectin have been demonstrated (Tarsio JF. et al., 1985, Diabetes, 34, 477-484; Tarsio JF. et al., 1988, Diabetes, 37, 532-539; Sternberg M. et al., 1995, C.R. Soc. Biol., 189, 967-985).
Thus, it is understood that in the course of aging of the skin, the physicochemical properties of collagen modify and this collagen becomes more difficult to dissolve and degrade.
Thus, one of the components of aged skin clearly appears to be glycated collagen.
It is very well known to this art that the skin results from a close combination between at least two components of which it is composed, namely, the epidermis and the dermis. The interactions between the dermis and the epidermis are such that it is reasonable to expect that a modification of one may have consequences on the other. It may be suspected that aging of the dermis, in particular with its glycation phenomena will inevitably have consequences on the epidermis with which is associated. In the course of aging of the skin, the glycation of collagen should result in modifications of the epidermis which are necessarily implicated in aging of the epidermis.
Thus, if the glycation of dermal proteins, particularly collagen, elicits nothing more than harmful consequences on the skin, similar consequences are to be expected of the glycation of the proteins in the structures associated with the skin such as, for example, the nails and/or the hair and, indeed, of any protein system.
It will thus be appreciated that need continues to exist for active agents/species which reduce or even inhibit the phenomenon of glycation of proteins.
It has now surprisingly and unexpectedly been determined that the hydroxystilbenes elicit the effect of reducing or even inhibiting the phenomenon of glycation of proteins.
Briefly, the present invention features the administration to an individual subject in need of such treatment, of an effective amount of at least one hydroxystilbene, or composition comprised thereof, to reduce or even inhibit the glycation of proteins, particularly the glycation of proteins of the skin and/or of the structures associated therewith.
This invention thus features a cosmetic/dermatological regime/regimen, comprising administering to an individual subject in need of such treatment, an effective amount of at least one hydroxystilbene, or composition comprised thereof, to reduce or even inhibit the glycation of dermal proteins, for example collagen, and/or the nails, and/or the hair, for example the keratins.
The present invention also features administration of an effective amount of at least one hydroxystilbene, or composition comprised thereof, to preventively and/or curatively treat the signs of aging of the skin or of its associated structures, which are implicated in glycation.
More particularly according to the present invention, the preferred hydroxystilbenes are compounds having the structural formula (I): 
in which n is an integer ranging from 0 to 4, inclusive and m is an integer ranging from 0 to 5, inclusive. These compounds can be in a cis- or trans-form.
According to the invention, by the term xe2x80x9chydroxystilbenexe2x80x9d are intended both the compounds of formula I and the hydroxyalkyl derivatives thereof.
The hydroxystilbenes are compounds that exist in the natural state in plants of the spermatophyte family and particularly in vine. Such compounds, for example such as resveratrol, exist in grapes and in wine.
The hydroxystilbenes are described in the prior art, inter alia, as depigmenting agents, (JP-87/192,040), as vasodilators (EP-96/830,517), as antithrobotic agents (JP-05/016,413), in the treatment of various cardiovascular afflictions (CA-2,187,990), as inhibitors of mutagenesis and carcinogenesis (JP-06/024,967) or, alternatively, are described as antioxidants.
Among these compounds, resveratrol (or 3,5,4xe2x80x2-trihydroxystilbene) is particularly known for the activities described above principally because it is a natural compound which exists in the skin of grapeseeds and in wine. In this regard, compare the review by Soleas and collaborators (Clinical Biochemistry, vol. 30, No 2, pp. 91-113, 1997) which well summarizes the state of the art regarding this compound and hydroxystilbenes.
However, the ability of the hydroxystilbenes to reduce or even inhibit the phenomenon of glycation was hitherto unknown.
Exemplary hydroxystilbenes according to this invention include the mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa- and nonahydroxystilbenes, and the hydroxyalkyl derivatives thereof.
Consistent herewith,the hydroxystilbenes can be administered either alone or as mixtures of any nature and can be of natural or synthetic origin.
Preferred hydroxystilbenes according to the invention include:
4xe2x80x2-hydroxystilbene,
2xe2x80x2,4xe2x80x2-dihydroxystilbene,
3xe2x80x2,4xe2x80x2-dihydroxystilbene,
4,4xe2x80x2-dihydroxystilbene,
2xe2x80x2,4 xe2x80x2,4-trihydroxystilbene,
3,4xe2x80x2,4-trihydroxystilbene,
2,4,4xe2x80x2,-trihydroxystilbene,
3,4,4xe2x80x2-trihydroxystilbene,
3,4xe2x80x2,5-trihydroxystilbene,
2xe2x80x2,3,4-trihydroxystilbene,
2,3xe2x80x2,4-trihydroxystilbene,
2xe2x80x2,2,4xe2x80x2-trihydroxystilbene,
2,4,4xe2x80x25-tetrahydroxystilbene
2xe2x80x2,3,4xe2x80x2, 5-tetrahydroxystilbene,
2,2xe2x80x2,4,4xe2x80x2-tetrahydroxystilbene,
3,3xe2x80x22,4xe2x80x25-tetrahydroxystilbene,
2,3xe2x80x2,4,4xe2x80x2-tetrahydroxystilbene,
3,3xe2x80x2,4,4xe2x80x2-tetrahydroxystilbene,
3,3xe2x80x2,4xe2x80x25,5xe2x80x2-pentahydroxystilbene,
2,2xe2x80x24,4xe2x80x2,6-pentahydroxystilbene,
2,3xe2x80x24,4xe2x80x26-pentahydroxystilbene,
2,2xe2x80x2,4,4xe2x80x2,6,6xe2x80x2-hexahydroxystilbene.
3,4xe2x80x25-Trihydroxystilbene, or resveratrol, is more preferred according to the invention.
The hydroxystilbene or composition comprised thereof are particularly well suited according to the invention for topical application onto the skin and/or the nails and/or the hair.
The amount of hydroxystilbene which is administered according to the invention naturally depends upon the desired effect and should be an amount which is effective in reducing or even inhibiting glycation.
For example, the amount of hydroxystilbene which can be used according to the invention advantageously ranges, for example, from 0.001% to 10% and preferably from 0.005% to 5% relative to the total weight of the composition.
In addition, the compositions of the invention are administered for a period of time which is sufficient to elicit the expected effects. To provide an order of magnitude, this duration can be a minimum of 3 weeks, but can also be more than 4 weeks, or even more than 8 weeks.
The subject compositions are especially well suited for cosmetic and dermatological applications, advantageously cosmetic applications.
The compositions of the invention suited for topical application contain a physiologically acceptable medium, i.e., a medium (vehicle, diluent or carrier) which is compatible with the skin, including the scalp, structures associated therewith, mucous membranes and/or the eyes and can constitute, in particular, a cosmetic or dermatological composition.
The subject compositions can be in any pharmaceutical form normally employed in cosmetics and dermatology, and can be, in particular, in the form of an optionally gelled aqueous solution, a dispersion of the lotion type which may contain two phases, an emulsion obtained by dispersing a fatty phase in an aqueous phase (O/W) or conversely (W/O), or a triple emulsion (W/O/W or O/w/O), or a vesicular dispersion of ionic and/or nonionic type. These compositions are prepared according to the usual methods.
The compositions of the invention can be formulated, for example, as a lotion, a gel, an ointment, a cream or a milk, a makeup-removing or cleansing lotion or milk, a shampoo, or a shower gel.
The present invention also features a cosmetic regime/regimen for treating the signs of aging associated with the glycation of proteins, particularly of the skin and/or the nails and/or the hair, comprising topically applying a cosmetic composition containing an effective amount of at least one hydroxystilbene onto the skin and/or the nails and/or the hair, such hydroxystilbene or composition thereof being present in such amounts as to inhibit glycation.
In order to further illustrate the present invention and the advantages thereof, the following specific example is given, it being understood that same is intended only as illustrative and in nowise limitative.
In said example to follow, all parts and percentages are given by weight, unless otherwise indicated.